Preclinical and clinical studies suggest that drugs that modulate the glutamatergic system might result in therapeutic effects in patients with mood disorders. Antidepressants have been demonstrated to have delayed indirect effects on this system. Lamotrigine, an inhibitor of glutamate release, is an approved treatment for bipolar disorder. Our group found in two separate open studies that the glutamate modulating agent riluzole (inhibitor of glutamate release, and enhancer of AMPA trafficking and glutamate reuptake) was effective in treatment-resistant unipolar and bipolar depression. Collectively, these data suggest that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents which more directly reduce glutamatergic neurotransmission, may represent a novel class of antidepressants. The efficacy of riluzole in treatment-resistant bipolar depression is currently being tested in a double-blind placebo-controlled study. Participants, ages 18 to 70 years with bipolar disorder currently in a major depressive episode are actively being recruited and randomized to double-blind, treated to receive either riluzole (50-200 mg/day) or placebo for a period of 8 weeks. Acute efficacy will be determined by demonstrating a greater response rate in the Montgomery-Asberg Depression Rating scale. This controlled study is still ongoing and actively recruiting subjects. The study blind has not been broken.